Biology:Interleukin 37
 Generic protein structure example |
Interleukin 37 (IL-37), also known as Interleukin-1 family member 7 (IL-1F7), is an anti-inflammatory cytokine important for the downregulation of pro-inflammatory cytokine production as well as the suppression of tumor cell growth.[1]
Gene location and structure
The IL-37 gene is in the human located on the long chromosome arm of chromosome 2. There has not been found any homolog gene in mice genome.[2] IL-37 undergoes alternative splicing with 5 different splice variants depending on which of the 6 possible exons are being expressed: IL-37a-e.[3] IL-37b is the largest and most studied one; it shares the beta barrel structure that is spread within the interleukin-1 family.[1]
Gene expression
IL-37a,b,c are being expressed in a variety of tissues - thymus, lung, colon, uterus, bone marrow. It is produced by immune cells, most of which are relevant to the immune inflammation response. Examples include natural killer cells, activated B lymphocytes, circulating blood monocytes, tissue macrophages, keratinocytes or epithelial cells.
Some IL-37 isoforms are tissue specific and have varying lengths depending on which exons are being expressed:
IL-37a is found in the brain. The isoform includes exons 3, 4, 5, and 6 and the isoform is 192 amino acids in length
IL-37b is found in the kidney, bone marrow, blood, skin, respiratory and urogenital tract. Exons 1, 2, 4, 5, and 6 are expressed and the isoform is 218 amino acids in length.
IL-37c is found in the heart, and contains exons 1, 2, 5, and 6 for a total amino acid length of 197.
IL-37d is found in the bone marrow and includes exons 1, 4, 5, and 6 for a total length of 197.
IL-37e is found in the testis and includes exons 1, 5, and 6 totaling 157 amino acids.[1][4]
Function
The mechanism of IL-37 functions is still to be elucidated. Known functions of IL-37 include anti-inflammatory effects, tumor suppression, and antimicrobial responses. IL-37 acts intracellulary and extracellulary, classifying the cytokine as dual-function.[1]
IL-37 Synthesis
IL-37, similar to other members of the interleukin-1 family, is synthesized by blood monocytes in a precursor form and secreted into the cytoplasm in response to inflammatory signaling. Examples of relevant inflammatory signals include TLR agonists, IL-1β, or TGF-β.[3] Full maturation requires cleavage by Caspase-1.[5]
Immune System Inhibition
IL-37 is known to have immunosuppression properties through two different binding mechanisms:
Interaction with IL-18 cell surface receptors - Intracellular IL-37 can be released from cells following necrosis or apoptosis.[4] IL-37 has two similar amino acid residues with IL-18, and thus extracellular IL-37 can interact with IL-18 receptor (IL-18R) and co-receptor IL-1 receptor 8 (IL-1R8). The affinity of IL-37b to IL-18R alpha subunit is much lower compared to IL-18. IL-37b interacts with IL-18 binding protein (IL-18BP), that is an antagonist of IL-18. The binding of IL-37b enhances the IL-18BP functions and can upregulate anti-inflammatory signals.[2][5]
Binding to SMAD3 receptor - Mature intracellular IL-37 can form functional complexes with phosphorylated or unphosphorylated Smad3,which can be transported to the cell nucleus. Nucleus IL-37 can have a direct inhibition function on the expression of pro-inflammatory cytokine gene transcription. Affected cytokines include IL-1β, IFN-γ, IL-6, and TNF-α.[3][6][4]
Tumor-Controlled Expression
IL-37 functions are active at low IL-37 concentrations. Higher concentrations leads to inactivation via dimer formation.[4] Experiments also show that certain cancer strains correspond to changes in IL-37 expression levels. Breast cancer and ovarian cancer are associated with elevated expression of IL-37. Colon cancer, lung cancer, Multiple Myeloma, and Hepatoma Carcinoma were correlated with decreased expression of IL-37 expression in affected areas.[3]
See also
- Interleukin-1 family
- Interleukin 18
- Interleukin 18 receptor
- Interleukin 18 binding protein
- Inflammation
- Carcinogenesis
References
- ↑ 1.0 1.1 1.2 1.3 "Interleukin-37: A crucial cytokine with multiple roles in disease and potentially clinical therapy". Oncology Letters 15 (4): 4711–4719. April 2018. doi:10.3892/ol.2018.7982. PMID 29552110.
- ↑ 2.0 2.1 "IL-37 is a fundamental inhibitor of innate immunity". Nature Immunology 11 (11): 1014–1022. November 2010. doi:10.1038/ni.1944. PMID 20935647.
- ↑ 3.0 3.1 3.2 3.3 "IL-37: An anti-inflammatory cytokine with antitumor functions". Cancer Reports 2 (2): e1151. April 2019. doi:10.1002/cnr2.1151. PMID 32935478.
- ↑ 4.0 4.1 4.2 4.3 "The Role, Involvement and Function(s) of Interleukin-35 and Interleukin-37 in Disease Pathogenesis". International Journal of Molecular Sciences 19 (4): 1149. April 2018. doi:10.3390/ijms19041149. PMID 29641433.
- ↑ 5.0 5.1 "The role of IL-37 in skin and connective tissue diseases". Biomedicine & Pharmacotherapy 122: 109705. February 2020. doi:10.1016/j.biopha.2019.109705. PMID 31918276.
- ↑ "Reviews of Interleukin-37: Functions, Receptors, and Roles in Diseases". BioMed Research International 2018: 3058640. 2018-04-01. doi:10.1155/2018/3058640. PMID 29805973.
Further reading
- "IL-37 requires the receptors IL-18Rα and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction". Nature Immunology 16 (4): 354–365. April 2015. doi:10.1038/ni.3103. PMID 25729923.
- "IL-37 is a fundamental inhibitor of innate immunity". Nature Immunology 11 (11): 1014–1022. November 2010. doi:10.1038/ni.1944. PMID 20935647.
- "A physical map of the region encompassing the human interleukin-1 alpha, interleukin-1 beta, and interleukin-1 receptor antagonist genes". Genomics 19 (2): 382–384. January 1994. doi:10.1006/geno.1994.1076. PMID 8188271.
- "Molecular cloning of the interleukin-1 gene cluster: construction of an integrated YAC/PAC contig and a partial transcriptional map in the region of chromosome 2q13". Genomics 41 (3): 370–378. May 1997. doi:10.1006/geno.1997.4654. PMID 9169134.
- "Identification and initial characterization of four novel members of the interleukin-1 family". The Journal of Biological Chemistry 275 (14): 10308–10314. April 2000. doi:10.1074/jbc.275.14.10308. PMID 10744718.
- "Identification and gene organization of three novel members of the IL-1 family on human chromosome 2". Genomics 66 (2): 213–216. June 2000. doi:10.1006/geno.2000.6184. PMID 10860666.
- "A tissue specific IL-1 receptor antagonist homolog from the IL-1 cluster lacks IL-1, IL-1ra, IL-18 and IL-18 antagonist activities". European Journal of Immunology 30 (11): 3299–3308. November 2000. doi:10.1002/1521-4141(200011)30:11<3299::AID-IMMU3299>3.0.CO;2-S. PMID 11093146.
- "IL-1H, an interleukin 1-related protein that binds IL-18 receptor/IL-1Rrp". Cytokine 13 (1): 1–7. January 2001. doi:10.1006/cyto.2000.0799. PMID 11145836.
- "Cloning and characterization of IL-1HY2, a novel interleukin-1 family member". The Journal of Biological Chemistry 276 (23): 20597–20602. June 2001. doi:10.1074/jbc.M010095200. PMID 11278614.
- "Two novel IL-1 family members, IL-1 delta and IL-1 epsilon, function as an antagonist and agonist of NF-kappa B activation through the orphan IL-1 receptor-related protein 2". Journal of Immunology 167 (3): 1440–1446. August 2001. doi:10.4049/jimmunol.167.3.1440. PMID 11466363.
- "A new nomenclature for IL-1-family genes". Trends in Immunology 22 (10): 536–537. October 2001. doi:10.1016/S1471-4906(01)02040-3. PMID 11574262.
- "A sequence-based map of the nine genes of the human interleukin-1 cluster". Genomics 79 (5): 718–725. May 2002. doi:10.1006/geno.2002.6751. PMID 11991722.
- "Genomic organization of the interleukin-1 locus". Genomics 79 (5): 726–733. May 2002. doi:10.1006/geno.2002.6752. PMID 11991723.
- "Interleukin-1F7B (IL-1H4/IL-1F7) is processed by caspase-1 and mature IL-1F7B binds to the IL-18 receptor but does not induce IFN-gamma production". Cytokine 18 (2): 61–71. April 2002. doi:10.1006/cyto.2002.0873. PMID 12096920.
- "A complex of the IL-1 homologue IL-1F7b and IL-18-binding protein reduces IL-18 activity". Proceedings of the National Academy of Sciences of the United States of America 99 (21): 13723–13728. October 2002. doi:10.1073/pnas.212519099. PMID 12381835. Bibcode: 2002PNAS...9913723B.
- "Proteomics-based identification of proteins interacting with Smad3: SREBP-2 forms a complex with Smad3 and inhibits its transcriptional activity". FEBS Letters 577 (1–2): 93–100. November 2004. doi:10.1016/j.febslet.2004.09.069. PMID 15527767.
External links
- Overview of all the structural information available in the PDB for UniProt: Q9NZH6 (Interleukin-37) at the PDBe-KB.
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